Process of preparing hydroxyphe-nylaminopropanols



iatented May I, 1934 I PROCESS OF PREPARING HYDROXYPHE- NYLAIVIINOPROPANOLS Max Bockmilhl, Gustav Ehrhart, and Leonhard Stein, Frankfort-on-the-Main, Germany, as signers to Winthrop Chemical Company, Inc., New York, N. Y., a corporation of New York No Drawing. Application November 19, 1932, Serial No. 643,520. In Germany May 21, 1930 9 Claims. (Cl. 260128.5)

The present invention relates to a process of propiophenone crystallizes from the residue; it

preparing hydroxyphenylaminopropanols. is recrystallized from hexahydrobenzene or alco- We have found that hydroxyphenylaminohol and then melts at 93 C. to 94 C. 60 propanols may be prepared by causing a halo- 40 grams of 3.4-dibenzyloxybromopropiophegen to act upon a compound of the followingnone are dissolved in 100 cc.of benzene; 36 grams formula: of dibenzylamine are added to the solution and the mixture is heated. in a reflux apparatus and X on a Water bath for about 6 hours. After several 65 hours standing, the dibenzylamine-hydrobro- 10 X COCHz-CH; mide which has separated is eliminated by filtering with suction and the filtrate is completely wherein at least one X stands for the group: freed from benzene. The residue is dissolved in OCH2CsI-I5, the remaining X for hydrogen, ether, the solution so obtained is washed with a 70 then causing dibenzylamine to act upon the halsmall quantity of water and then dried by means ogenated compound thus obtained and reducing of sodium sulfate. Hydrochloric acid gas is inthe 2-dibenzylaminopropiophenone thus obtained troduced into the dried solution until an acid with hydrogen in the presence of a noble metal reaction is obtained. The hydrochloride which catalyst. crystallizes is separated by filtering with suc- 75 The noble metal catalyst, for instance platition and suspended in water. By an addition of num or palladium, may be applied in a finely ammonia the base is again set free, and is disdivided form or in the form of its oxide. Among solved in ether. The solution is dried over sothe agents, known to bind acids, there may be dium sulfate and the ether is distilled. The

mentioned metal carbonates and metal oxides 3. l-dibenzyloxydibenzylaminopropiophenone soon such as calcium carbonate, sodium bicarbonate, crystallizes. It is recrystallized from methanol 25 barium carbonate, magnesium oxide, zinc oxide and then melts at 84 C. to 86 C. The hydro or the like. chloride is obtained by neutralizing the base with The products obtainable by the process of this the calculated quantity of alcoholic hydrochloric invention are remedies, or intermediate prodacid.

ucts for the manufacture of therapeutically val- 10 grams of 3.4-dibenzyloxydibenzylamino- 30 uable substances. propriophenone hydrochloride are dissolved in The following examples illustrate the inven- 250 cc. of alcohol and hydrogenated with hydrotion: gen in the presence of a palladium catalyst. When 1. 34.6 grams or" 3.4-dibenzyloxypropiophenone the calculated quantity of hydrogen has been 90 are dissolved in 300 cc. of methylene chloride; absorbed, the catalyst is removed by filtering 12 grams of calcium carbonate are added to the with suction and the alcoholic solution is evapsolution and 16 grams of bromine are then enorated to dryness in a vacuum. By recrystaltered drop by drop, while stirring. As soon. as lizing the residue from a mixture of methanol the reaction is complete, the calcium compounds and acetone, the 3.4-dihydroxyphenylaminoproare eliminated by filtering with suction and the panol hydrochloride is obtained melting at 178 40 methylene chloride solution is entirely evapo- C. The reaction proceeds according to the folrated. On cooling, the 3.4-dibenzy1oxybromolowing equations:

HaOaHs The liquid is freed from the precipitate by filtration and washed with a dilute sodium bicarbonate solution and water. The carbon tetrachloride solution is dried by means of sodium sulfate and concentrated under strongly reduced pressure. The residue obtained is parabenzyloxychloropropiophenone which solidifies after some time in a crystaline state. 27 grams of the chloro compound are dissolved in 50 cc. of alcohol and the solution is mixed with 39 grams of distilled dibenzylamine. The mixture is allowed to stand over-night and the dibenzylamine hydrochloride which has formed is precipitated by an addition of ether. The mass is filtered by suction and subsequently washed with ether. The solution in ether is washed with water, dried with the aid of sodium sulfate and concentrated in a vacuum. The residue is stirred with a low-boiling petroleum ether. The portion which is insoluble in petroleum ether is neutralized with alcoholic hydrochlorioc acid, diluted with alcohol and. hydrogenated with hydrogen in the presence of a palladium catalyst. The compound obtained by the reduction is para-hydroxyphenylaminopropanol hydrochloride which, after recrystallization from methanol and ether, melts at 207 C.

3. 20 grams of meta-benzyloxypropiophenone are dissolved in 200 cc. of methylene chloride and 4.8 cc. of bromine are added to the solution drop by drop, while stirring. As soon as the coloration of bromine has disappeared, the methylene chloride solution is washed with a sodium bicarbonate solution and water. The liquid is dried by means of sodium sulfate and concentrated in a vacuum. The residue is meta-benzyloxybromopropiophenone. 32 grams of the compound obtained are dissolved in 50 cc. of alcohol and the solution is mixed with 39 grams of dibenzylamine. After several hours standing, the reaction is complete. By a addition of ether, the dibenzylamine hydrobromide formed by the reaction is precipitated and filtered by suction. The ethereal solution is washed with water, dried over sodium sulfate and evaporated. The residue is stirred with a low-boiling petroleum ether. The product which is insoluble in petroleum ether is neutralized with alcoholic hydrochloric acid and hydrogenated with hydrogen in an alcoholic solution in the presence of a palladium catalyst. When the absorption of hydrogen is complete, the catalyst is removed by filtration and the alcoholic solution is concentrated in a vacuum. The residue is meta-hydroxyphenyl-aminopropanol hydrochloride which, after recrystallization from propyl alcohol and ether, melts at 178 C.

We claim:

1. In the process of preparing hydroxy-phenylamino-propan-ols the steps which comprise causing a halogen to act upon a compound of the following formula:

X OO-CHPCHZ.

wherein one X stands for the group OCH2 C H5, and the remaining X for hydrogen or the group O-CH2C6H5, then causing dibenzylamine to act upon the halogenated compound and reducing the 2-dibenzylamino-propiophenone thus obtained with hydrogen in the presence of a noble metal catalyst.

2. In the process of preparing hydroxy-phenylamino-propan-ols the steps which comprise causing a halogen to act upon a compound of the following formula:

X CO-CHr-CH3.

wherein one X stands for the group OCH2- CeH5, and the remaining X for hydrogen or the group O-CH2C6H5, then causing dibenzylamine to act upon the brominated compound and reducing the 2dibenzylaminopropiophenone thus obtained with hydrogen in the presence of a noble metal catalyst.

4. In the process of preparing hydroxy-phenylamino-propan-ols the steps which comprise causing bromine to act upon a compound of the following formula:

wherein one X stands for the group -OCH2C6H5,

and the remaining X for hydrogen or the group OCH2C6H5, in the presence of calcium carbonate, then causing dibenzylamine to act upon the brominated compound and reducing the 2-dibenzylaminopropiophenone thus obtained with hydrogen in the presence of a noble metal catalyst.

6. In the process of preparing hydroxy-phenylamino-propan-ols the steps which comprise 150 causing bromine to act upon a compound of the following formula:

X CO.CH2CH wherein one X stands for the group -O-CH2C6H5,

and the remaining X for hydrogen or the group -O-CH2C6H5, in the presence of calcium carbonate, then causing dibenzylamine to act upon the brominated compound and reducing the 2-dibenzylaminopropiophenone thus obtained with hydrogen in the presence of a palladium catalyst.

7. In the process of preparing 3.4-dihydroxyphenyl-amino-propanol the steps which comprise causing bromine to act upon 3.4-dibenzyloxypropiophenone in the presence of calcium carbonate, then causing dibenzylamine to act upon the resulting 3.4-dibenzyloxybrompropiophenone and reducing the 3.4-dibenzyloxy-dibenzylaminopropiophenone thus obtained with hydrogen in the presence of a palladium catalyst.

8. In the process of preparing 3-hydroxyphenylaminopropanol the steps which comprise causing bromine to act upon B-benzyloxypropiophenone in the presence of sodium bicarbonate, then causing dibenzylamine to act upon the resulting 3-benzyloxybrompropiophenone and reducing the 3-benzyloxydibenzylaminopropiophenone thus obtained with hydrogen in the presence of a palladium catalyst.

9. In the process of preparing 4-hydroxyphenylaminopropanol the steps which comprise causing bromine to act upon i-benzyloxypropiophenone in the presence of calcium carbonate, then causing dibenzylamine to act upon the resulting 4-benzyloxybrompropiophenone and reducing the 4-benzyloxydibenzylaminopropiophenone thus obtained with hydrogen in the presence of a palladium catalyst.

MAX BOCKM'UHL. GUSTAV EHRHART. LEONHARD STEIN. 

